Method and an apparatus for determining the content of a constituent of blood of an individual

ABSTRACT

A method and an apparatus for determining the content of a constituent of blood of an individual are disclosed. In the method a whole blood stream is extracted from a blood vessel of said individual, the stream being directed through a path defining a substantially non-varying flow-through area wherein is provided a flow-through measuring cuvette including opposite first and second optical transparent surface parts defining an optical transmission path of the order of 0.5-2.0 mm. The whole blood stream flowing through the measuring cuvette is irradiated by irradiating the first optical transparent surface part of the measuring cuvette with multi-wavelength near infrared light. The near infrared absorption spectrum is detected and the content of the constituent is quantified on the basis of the detected near infrared absorption data. The method is particularly suited for measuring constituents of whole blood in an extracorporeal loop, for example in hemodialysis.

The present invention relates to novel techniques of determining thecontent of a constituent of blood of an individual and in particular anovel technique of determining the content of a constituent of blood ofa hemodialysis patient.

Individuals suffering from kidney malfunction are treated by dialysis.By the conventional dialysis method, the blood of the patient inquestion is rinsed by means of a dialysis machine as the blood iscontacted with a liquid known as the dialysate through a permeablemembrane causing constituents of the blood to permeate through themembrane and be absorbed by substances of the dialysate. Reference ismade to "Encyclopedia of Medical Devices and Instrumentation", vol. 31695-1711 (1988) (Reference 4) in which a detailed discussion of thedialysis technique is presented.

In accordance with the conventional dialysis technique, the patient hashis or her blood rinsed for a predetermined period of time which periodof time is determined solely an empirical basis. Prior to the dialysistreatment, a blood sample may be collected from the patient which bloodsample is analysed and similarly, a blood sample may be collected fromthe patient after the dialysis treatment has been finished. Throughcomparison of the two blood samples, the result of or the outcome of thedialysis treatment may be evaluated.

In numerous other situations such as during thorax surgery, a similarsituation exists when blood is circulated extracorporeally through aheart-lung machine in order to replace or assist, for a limited timeperiod, the heart or lung function.

An object of the present invention is to provide a novel techniquerendering it possible to carry out a real-time or a quasi real-timeanalysis or determination of the content of a constituent of blood of anindividual having his or her blood rinsed in a dialysis machine.

A further object of the present invention is to provide a noveltechnique rendering it possible to perform a real-time or a quasireal-time analysis or determination of the content of a constituent ofblood of a patient when exposed to surgery or similarly having a wholeblood stream of the order of 50-1,000 ml/min extracted from a bloodvessel.

A feature of the present invention relates to the fact that the noveltechnique according to the present invention renders it possible toperform a multiconstituent analysis of blood of an individual inreal-time or quasi real-time and further to compensate for anyfluctuations of the blood flow of the blood stream.

A particular advantage of the present invention relates to the fact thatin accordance with the teachings of the present invention, the dialysistreatment of a patient may be monitored in real-time or quasi real-timeas a continuous determination or analysis of the constituent of bloodsuch an the content of urea or any other relevant constituent may bedetermined in real-time or quasi real-time.

The above objects, the above feature and the above advantage togetherwith numerous other objects, features and advantages which will beevident from the below description are in a first aspect of theinvention obtained by a method of determining the content of aconstituent of blood of an individual, comprising:

extracting a whole blood stream of the order of 50-1,000 ml/min from ablood vessel of said individual,

directing said whole blood stream through a flow path defining asubstantially non-varying flow-through area and comprising aflow-through measuring cuvette constituting part of said flow path, saidflow-through measuring cuvette including opposite first and secondoptically transparent surface defining an optical transmission path ofthe order of 0.5-2.0 mm,

irradiating said first optically transparent surface part of saidflow-through measuring cuvette with multi-wavelength near infrared lightso as to expose said whole blood stream flowing through saidflow-through measuring cuvette to said multi-wavelength near infraredlight,

detecting the near infrared absorption spectrum represented by nearinfrared absorption data of said whole blood stream flowing through saidflow-through measuring cuvette, and

quantifying said content of said constituent by inputting said nearinfrared absorption data into a mathematical model representing therelation between the near infrared absorption data and the content ofsaid constituent.

The above objects, the above feature and the above advantage togetherwith numerous other objects, features and advantages are in a secondaspect of the invention obtained by a method of determining the contentof a constituent of blood of an individual, comprising:

extracting a whole blood stream of said individual from a blood vesselof said individual,

directing said whole blood stream through a flow path comprising aflow-through measuring cuvette constituting part of said flow path, saidflow-through measuring cuvette including at least one, opticallytransparent surface part,

propelling said whole blood stream through said flow path by means of apump causing said whole blood stream to flow through said flow path in apulsed mode,

monitoring said flow of said whole blood stream through saidflow-through measuring cuvette of said flow path, so as to determineperiods of substantially constant flow of said whole blood streamthrough said flow-through measuring cuvette,

irradiating said at least one optically transparent surface part of saidflow-through measuring cuvette with electromagnetic radiation of aspecific spectral composition, so as to expose said whole blood streamflowing through said flow-through measuring cuvette to saidelectromagnetic radiation,

detecting the electromagnetic radiation absorption spectrum, representedby electromagnetic radiation absorption data, of said whole blood streamflowing through said flow-through measuring cuvette at said periods ofsubstantially constant flow of said whole blood stream flowing throughsaid flow-through measuring cuvette, and

quantifying said content of said constituent by inputting saidelectromagnetic radiation absorption data into a mathematical modelrepresenting the relation between electromagnetic radiation absorptiondata and the content of said constituent.

The above objects, the above feature and the above advantage togetherwith numerous other objects, features and advantages which will beevident from the below description are in a third aspect of theinvention obtained by an apparatus for determining the content of aconstituent of blood of an individual, comprising:

means for extracting a whole blood stream from a blood vessel of saidindividual,

a flow path defining a substantially non-varying flow-through area,

means for directing said whole blood stream through said flow path,

a flow-through measuring cuvette constituting a part of said flow path,said flow-through measuring cuvette including opposite first and secondoptically transparent surface parts defining an optical transmissionpath of the order of 0.5-2.0 mm,

means for generating and irradiating said first optically transparentsurface part of said flow-through measuring cuvette withmulti-wavelength near infrared light so as to expose said whole bloodstream flowing through said flow-through measuring cuvette to saidmulti-wavelength near infrared light,

detector means for detecting the near infrared absorption spectrum ofsaid whole blood stream flowing through said flow-through measuringcuvette represented by near infrared absorption data, and

quantifying means for quantifying said content of said constituent byinputting said near infrared absorption data into a mathematical modelrepresenting the relation between near infrared absorption data and thecontent of said constituent.

The above objects, the above feature and the above advantage togetherwith numerous other objects, features and advantages are in a fourthaspect of the invention obtained by an apparatus for determining thecontent of a constituent of blood of an individual, comprising:

means for extracting a whole blood stream of said individual from ablood vessel of said individual,

a flow path,

means for directing said whole blood stream through said flow path,

a flow-through measuring cuvette constituting part of said flow path,said flow-through measuring cuvette including at least one opticallytransparent surface part,

means for directing said whole blood stream through said flow path,

means for propelling said whole blood stream through said flow path,causing said flow-path to flow through said flow path in a pulsed mode,

monitor means for monitoring said flow of said whole blood streamthrough said flow-through measuring cuvette of said flow path, so as todetermine periods of substantially constant flow of said whole bloodstream flowing through said flow-through measuring cuvette,

means for generating and irradiating said at least one opticallytransparent surface part of said flow-through measuring cuvette withelectromagnetic radiation of a specific spectral composition, so as toexpose said whole blood stream flowing through said flow-throughmeasuring cuvette to said electromagnetic radiation of said specificspectral composition,

detector means for detecting the electromagnetic radiation absorptionspectrum, represented by electromagnetic radiation absorption data, ofsaid whole blood stream flowing through said flow-through measuringcuvette at said periods of substantially constant flow of said wholeblood stream flowing through said flow-through measuring cuvette, and

quantifying means for quantifying said content of said constituent byinputting said electromagnetic radiation absorption data into amathematical model representing the relation between electromagneticradiation absorption data and the content of said constituent.

The above objects, the above feature and the above advantage togetherwith numerous other objects, features and advantages are in a fifthaspect of the invention obtained by a method of hemodialysis,comprising:

extracting a whole blood stream of the order of 50-1,000 ml/min from ablood vessel of an individual,

directing said whole blood stream through an extracorporeal flow path toa hemodialyser through a flow path comprising a flow-through measuringcuvette constituting part of said flow path, said flow-through ensuringcuvette including opposite first and second optically transparentsurface part defining and optical transmission path of the order of0.5-2.0 mm,

irradiating said first optically transparent surface part of saidflow-through measuring cuvette with multi-wavelength near infrared lightcomprising light of the wavelength range 700-1,800 nm such as1,400-1,600 nm so as to expose said whole blood stream flowing throughsaid flow-through measuring cuvette to said multi-wavelength nearinfrared light,

detecting the near infrared absorption spectrum of said whole bloodstream flowing through said flow-through measuring cuvette representedby near infrared absorption data,

quantifying the content of urea of said whole blood stream by inputtingsaid near infrared absorption data into a mathematical modalrepresenting the relation between near infrared absorption data and thecontent of urea.

According to a sixth aspect of the present invention, a flow-throughmeasuring cuvette is provided for use in either of the above methods orapparatuses said flow-through measuring cuvette defining a substantiallynon-varying flow-through area and including opposite, opticallytransparent surface parts defining a substantially non-varying opticaltransmission path of the order of 0.5-2.0 mm.

In accordance with the present invention, it has been realized that awhole blood/real-time determination of the content of a constituent ofblood of an individual such as a patient suffering from kidneymalfunction and being subjected to dialysis treatment my be carried outby a multi-wavelength near infrared analysis technique performed as ablood stream of the order of 50-1,000 mL/min is directed in its entiretythrough an optical transmission path of the order of 0.5-2.0 mm.

For handling the blood flow stream in question, the non-varying flowthrough area is preferably of the order of 5-20 mm², such as 12-17 mm²,corresponding to the flow-through area of conventional dialysis tubing.

It has in accordance with the teachings of the present invention beenrealized that it is of the outmost importance that the blood of thewhole blood stream which is analysed for determining the content of theconstitutent in question of the blood of the individual in questionshould not be exposed to excessive pressure and/or velocity alterationsor variations such as extreme acceleration or deceleration whichinevitably result in deterioration or destruction of the blood of theindividual in question.

The detection of the near infrared or alternatively the electromagneticabsorption spectrum which constitutes a basis for the quantifying of thecontent of the constituent in question may be based on transmission orreflection detection techniques in accordance with well known opticaldetection principles per se.

In a preferred embodiment of the invention the mathematical model allowsfor determination of several constituents at a time. The relevantconstituents are selected from the group of urea, glucose, lactate,total protein, lipids, osmolality and hemoglobins.

According to the presently preferred embodiments of the second andfourth aspect of the present invention, the detection of theelectromagnetic radiation absorption spectrum is based on a transmissiondetection of the electromagnetic radiation transmitted through the bloodflow stream flowing through the substantially non-varying opticaltransmission path as the flow-through measuring cuvette comprisesopposite first and second optically transparent surface parts anddefines a substantially non-varying optical transmission path, and asthe detection of the electromagnetic radiation absorption spectrum isdetermined by detecting the transmission of the electromagneticradiation through the whole blood stream flowing through theflow-through measuring cuvette through the optical transmission paththereof.

The cuvette which constitutes the above sixth aspect of the presentinvention and which also constitutes an element of the methods andapparatuses according to the above first, second, third, fourth andfifth aspects of the present invention preferably constitutes an elementfulfilling the above requirements as to low or substantially lowpressure or velocity impact to the blood which is guided through thecuvette. Thus, the flow-through cuvette according to the presentinvention preferably comprises a central section including said oppositefirst and second optically transparent surface parts, tubular inlet andoutlet sections and first and second transition sections, said first andsecond transition sections constituting sections connecting said inletand outlet sections, respectively, to said central section andpresenting gradually changing sectional shapes generating to nosubstantial extent pressure or velocity gradients to said whole bloodstream flowing through said flow-through cuvette so am to eliminate toany substantial extent any blood degradating pressure or velocity impactto said blood flow.

According to the presently preferred embodiments of the above aspects ofthe present invention, the detection of the absorption spectrum being anear infrared absorption spectrum or alternatively anotherelectromagnetic absorption spectrum of the whole blood stream flowingthrough the flow-through measuring cuvette preferably comprisesdetecting the spectrum represented by a first sat of spectral data oflight transmitted through the whole blood stream flowing through theflow-through measuring cuvette and irradiated from the second opticallytransparent surface part of the flow-through measuring cuvette.

The detection of the absorption spectrum may be based on a previousdetection of the spectral composition of the radiation irradiated to theflow-through measuring cuvette. Alternatively and preferably, thedetection of the absorption spectrum of the whole blood stream flowingthrough the flow-through measuring cuvette preferably comprisesdetecting the spectrum represented by a second set of spectral data ofthe electromagnetic radiation irradiated to the first opticallytransparent surface part of the flow-through measuring cuvette thusrendering it possible to compensate for any variation of the radiationcaused by for example ageing of the radiation source.

The detection of the absorption spectrum preferably further comprisesgenerating the absorption data representing the absorption spectrum inquestion from the first set of spectral data and from the second sot ofspectral data, thus compensating for any radiation source changing orageing effects. The generation of the absorption data from the first andsecond sets of spectral data is preferably performed by subtracting thefirst sat in logaritmic representation from the second set in logaritmicrepresentation, thus providing the absorption data.

In accordance with optical detection techniques well known in the art,the detection of the absorption spectrum of the whole blood streamflowing through the flow-through measuring cuvette preferably furthercomprises detecting the spectrum represented by a third set of spectraldata of light irradiated from the second optically transparent surfacepart of the flow-through measuring cuvette at periods of time in whichthe first optically transparent surface of the flow-through measuringcuvette is not irradiated. The third set of spectral data, thus,represents a reference state, i.e. a state under which no radiationshould be detected. The third set of spectral data, thus, constitutes adarkness reference data not which further provides zero currentcompensation of the detector or detectors used for detecting theradiation.

The darkness compensation and zero current compensation techniquepreferably further comprises subtracting the third set of spectral datafrom both the first set of spectral data and from the second set ofspectral data, thereby providing corrected first and second sets ofspectral data from which the absorption data is provided as previouslydiscussed.

The detection of the absorption spectra being near infrared absorptionspectra or alternatively electromagnetic absorption spectra is based onspectrophotometrical measuring technique. The spectrophotometricalmeasuring technique may be performed in accordance with numerousspectrophotometric techniques well known in the art, such as FT (Fouriertransformation) spectrophotometric technique, Hadamard transformationspectrophotometric technique, AOTF (Acoustic Optical Tunable Filter)spectrophotometric technique, diode array spectrophotometric techniqueincluding reverse optical measuring technique, scanning dispersivespectrophotometric technique or similar spectrophotometric technique.

The mathematical model on the basis of which the content of theconstituent in question is quantified is preferably established on thebasis of a training sat of samples having relevant known variations incomposition and thus producing relevant absorption spectra. Thequantifying of the content of the constitutent in question preferablycomprises mathematical analysis techniques such as multivariate dataanalysis technique, e.g. PLS analysis technique (Partial Least Square),PCR analysis technique (Principal Components Regression), MLR analysistechnique (Multiple Linear Regression), artificial neural networkanalysis technique or similar analysis technique. The mathematicalquantifying technique may be performed in accordance with the techniquedescribed in U.S. Pat. No. 4,975,581 to which reference is made andwhich is hereby incorporated in the present specification by reference.

According to the fifth aspect of the present invention, the dialysistreatment may be controlled on the basis of the determination of thecontent of urea of the whole blood stream as the hemodialysis treatmentmay be continued until the content of urea of the whole blood stream isdecreased below a specific threshold.

The spectrophotometrical detection technique is preferably as will beevident from the below detailed description performed in accordance withthe teaching described in U.S. Pat. No. 4,977,281, to which reference ismade and which is hereby incorporated in the present specification byreference. Relevant and interesting detection and measuring techniquesare disclosed in U.S. Pat. No. 5,105,054, U.S. Pat. No. 4,745,279, U.S.Pat. No. 4,717,548, U.S. Pat. No. 4,056,368, EP 0 495 503, EP 0 457 804,EP 0 419 223, EP 0 419 222, EP 0 238 809, DE 2825134. Reference is madeto the above U.S., EP and DE patents and the above U.S. patents arehereby further incorporated in the present description by reference.

BRIEF DESCRIPTION OF THE DRAWING

The invention will now be further described with reference to thedrawings, in which

FIG. 1 is a schematic vie of a whole blood analyzing apparatusillustrating the intentional application of the whole blood analyzingapparatus in connection with monitoring a hemodialytic process,

FIG. 2 is a perspective view of a beam-splitting chopper section of thewhole blood analyzing apparatus shown in FIG. 1,

FIG. 3 is a perspective view of a spectrophotometric section of thewhole blood analyzing apparatus shown in FIG. 1,

FIG. 4 is a perspective view of a supply pump of a hemodialysis machinealso illustrating a measuring cuvette of the whole blood analyzingapparatus shown in FIG. 1 and further a pulse detector,

FIG. 5 is a perspective and schematic view of a light-transmittingassembly,

FIG. 6 is a perspective and schematic view of a light-reflectingassembly,

FIG. 7 is a block diagrammatic view of the electronic circuitry of thespectrophotometric section shown in FIG. 3,

FIG. 8 is a diagrammatic view of an electronic circuitry section of thedual beam chopper section shown in FIG. 2,

FIGS. 9-13 are diagrammatic views of spectra recorded by means of thewhole blood analyzing apparatus shown in FIG. 1,

FIG. 14 is a perspective view of the measuring cuvette of the wholeblood analyzing apparatus shown in FIG. 1, and

FIG. 15 is a flow chart representation of the software of the personalcomputer controlling the over-all operation of the whole blood analyzingapparatus shown in FIG. 1.

In FIG. 1, a prototype embodiment of a whole blood analyzing apparatusis shown implemented in accordance with the teaching of the presentinvention. The blood analyzing apparatus is shown in the upper part ofFIG. 1 and comprises a dual beam chopper section 100, shown in theuppermost part of FIG. 1 and shown in greater details in FIG. 2, aspectrophotometric section, shown in the central part of FIG. 1 andshown in greater details in FIG. 3, a computer section comprising apersonal computer, shown in the central, right-hand part of FIG. 1, forcarrying out a data processing of data produced by thespectrophotometric section, in accordance with the analyzing techniqueknown as partial least-square methods for spectral analysis, vide e.g.references 1, 2 and 3, and a measuring cuvette 24, shown in the centralpart of FIG. 1 below the spectrophotometric section and also shown ingreater details in FIG. 14. The cuvette 24 is interfaced between thedual beam chopper section 100 and the spectrophotometric section and isinterconnected between a hose pump or peristaltic pump 50 and a dialysisapparatus 10, which hose pump 50 supplies blood from a patient to thedialysis apparatus 10. The hose pump 50 and the dialysis apparatus 10are shown in the lowermost part of FIG. 1. The dialysis apparatus 10comprises a conventional dialysis machine 40, which communicates with ablood vessel of a patient or parson who needs dialysis treatment. Thereference numeral 12 designates a forearm of the patient or person inquestion.

From the forearm 12 of the patient or person, blood is extracted througha cannula 14 and supplied through a hose 16 to an arterial pressuremonitor 18 and further through a hose 20 to the hose pump 50. The hosepump 50 comprises a housing 52, in which the hose 20 is received,defining a hose loop 21 communicating with propelling pressure rollers56 and 58 supported on a pressure-roller support body 54 of the hosepump 50.

The hose 20 and the hose loop 21 further communicates with a hose 22,establishing connection to the cuvette 24, through which the bloodextracted from the forearm 12 is guided in a laminar flow of nosubstantial pressure or volume flow reduction further to a hose 26,through which the blood is input to the dialysis machine 40 of thedialysis apparatus 10, in which dialysis machine the blood in rinsed anthe blood communicates with a dialysis fluid through hemodialysismembranes in accordance with the hemodialysis technique well-known inthe art per se.

The dialysis fluid in input to the dialysis machine 40 through an inlethose 28 and output from the dialysis machine 40 through an outlet hose30. The blood, which has been subjected to hemodialysis treatment in thedialysis machine 40, is output from the dialysis machine 40 through afurther hose 32, which supplies the partly rinsed blood to an air andfoam detector 34, serving the purpose of preventing that air bubbles orfoam are present in the blood, which is returned through a hose 36 and acannula 38 to a blood vassal at the forearm 12 of the patient or personin question.

The dialysis fluid and the blood input to the hemodialysis machine 40are guided through the hemodialysis machine 40 in counterflow. Withinthe dialysis machine 40, separate components are defined, which aredesignated the reference numerals 41, 42, 43, 44 and 45. Thecompartments 41, 43 and 45 constitute compartments in which the blood isforced in counterflow in relation to the dialysis fluid, which is forcedthrough the compartments 42 and 44 from the inlet hose 28 to the outlethose 30.

The cuvette 24, which in shown in greater details in FIG. 14,constitutes a central or essential component of the whole bloodanalyzing apparatus. The configuration of the cuvette prevents that theblood is accelerated, decelerated or subjected to pressure or volumetricgradient, which might cause severe damage to the blood cells of theblood. The cuvette is further adapted for NIR infraredspectrophotometric analysis of the blood for analyzing the constituentsof the blood and consequently for monitoring the hemodialysis process,which is carried out by means of the dialysis machine 40. By themonitoring and analyzing of the hemodialysis operation, a more adequateand efficient hemodialysis operation may be carried out, since thehemodialysis operation may be carried out for a period of the necessaryto reduce the contents of specific blood constitutents to levels belowpreset threshold levels. Furthermore, the continuous monitoring andanalyzing technique which may be carried out by means of the whole bloodanalyzing apparatus implemented in accordance with the teaching of thepresent invention renders it possible to stop the hemodialysis operationas the above threshold levels have bean reached, contrary to theconventional hemodialysis operation, in which the hemodialysis operationis carried out for a period of time which is based on a pure estimatebased on a blood sample analysis and empirical realizations regardingthe relations between hemodialysis time periods and reductions of thecontents of specific blood constituents.

The cuvette 24 in of a structure in which the optical path in of theorder of 1 mm, rendering it possible to carry out a NIR infraredspectrophotometric analysis of the blood which is caused to flow throughthe cuvette 24 without any substantial pressure gradients beinggenerated by the presence of the cuvette 24 within the blood supply linefrom the hose pump 50 to the dialysis machine 40.

The hose pump 50 in shown in greater details in FIG. 4. The rollersupport body 54 of the hose pump 50 in caused to rotate, as the rollersupport body 54 is connected to a shaft 53 of a motor 51. As the rollersupport body 54 is caused to rotate in the clockwise direction in FIGS.1 and 2, the blood is caused to be forced from the hose 20, whichconstitutes a blood inlet hose, through the hose loop 21 and furtherthrough the hose 22, which constitutes an outlet tube, towards thecuvette 24.

The position of the roller body 54 and consequently the rollers 56 and58, propelling the blood through the hose loop 21, in detected by meansof a stem body 59, which constitutes an integral, outwardly protrudingpart of the roller support body 54, and which engages with two switches60 and 62, serving the purpose of providing electrical signalsrepresenting the position of the stem body 59 and consequently theposition of the roller support body 54.

The switches 60 and 62 generate pulses, which constitute pulse trainsrepresenting the actual position of the rollers 54 and 56 and furtherthe rotational notion of the roller support body 54. The switches 60 and62 are arranged so as to generate pulses as the stem body 59 engageswith the switch in question, said pulses representing the position ofthe roller support body 54, in which a pressure wave is generated in theblood supplied from the hose pump as the rollers 56 and 58 aredisengaged from the hose loop 21.

The pulses generated by the switches 60 and 62 are supplied throughelectrical signal lines 61 and 63, respectively, to a PLL (phase lockedloop) synchronizing circuit block 64, the purpose of which will beevident from the below description.

The dual beam chopper section 10, shown in the uppermost part of FIG. 1and further in FIG. 2, comprises a light-generating lamp 102, preferablyconstituted by a halogen bulb generating visible light, i.e.electromagnetic radiation within the wavelength interval 400-700 nm, NIR(NIR infrared radiation), i.e. electromagnetic radiation within thewavelength interval 700-2500 nm and IR (infrared radiation), i.e.electromagnetic radiation within the wavelength interval 2500-10000 nm.The lamp 102 is supplied from a power supply 98.

The electromagnetic radiation generated by the lamp 102 is focussed intwo light beams, a first one of which is generated by means of a mirror104 and a focusing lens 108, and a second one of which in generated bymeans of a mirror 106, similar to the mirror 104, a lens 110, similar tothe lens 108 and a mirror 112. The first light beam is designated thereference numeral 109 and is directed from the lens 108 through a filter114, removing electromagnetic radiation from the wavelength range200-450 nm, and is directed through a further focussing lens 118. Thesecond light beam is designated the reference numeral 113 and isdirected through a filter 116, similar to the filter 114, and is furtherdirected through a further focusing lens 120, similar to the focusinglens 118.

The first light beam 109 and the second light beam 113 focussed by meansof the focussing lenses 118 and 120, respectively, are chopped by meansof a chopper disc 122. The chopper disc 122 serves the purpose ofallowing transmission of the first and the second light boom to arespective optical fibre and of interrupting the light beams andconsequently preventing light from being transmitted to the opticalfibre in question. For generating the light-beam chopper effect, thechopper disc 122 is provided with a slit 132, which constitutes a 90°segment of the chopper disc. The chopper disc 122 in caused to rotate,driven by a motor assembly 136, which is provided with a gear assembly137, serving the purpose of reducing the rotational speed of a motorshaft of the motor assembly 136 to a fairly low rotational speed of anoutput shaft of the gear assembly 137, on which output shaft the chopperdisc 122 is mounted. The chopper disc in caused to rotate at arotational speed of approximately 50-250 rpm in dependency of theoperation of the hose pump. As the chopper disc 122 rotates, the lightbeams 109 and 113 are sequentially transmitted to a first optical fibre220 and a second optical fibre 222, respectively. For receiving thelight beams 109 and 113, the optical fibres 220 and 222 are providedwith optical fibre fittings 221 and 223, respectively.

Apart from the light-transmitting slit 132, the chopper 122 is providedwith a light-reflecting surface area 134 and two outwardly protrudingrim parts 124 and 126, which are separated by circumferential recesses128 and 130. The outwardly protruding rim parts 124 and 126 and thecircumferential recesses 128 and 130 communicate with two detectors 140and 143, which serve the purpose of detecting the presence of outwardlyprotruding rim parts 124 and 126 received within the detector inquestion. The detectors 140 and 143 are based on the optical principleas will be evident from the below description of the detectors 140 and143, which are shown in greater details in FIG. 8. The detectors 140 and143 may be based on different detector principles, such as capacitive,inductive or proximity detector principles.

The light-transmitting surface area 134 communicates with a furtherdetector 146, which constitutes a detector, including a light source anda light detector, and which is also in greater details in FIG. 8.

The detectors 140, 143 and 146 serve the overall purpose of generatingpulses representing the actual position of the chopper disc 122. Thepulses generated by the detectors 140, 143 and 146 are input to adetector circuit block 150, which also communicates with the PLLsynchronizing circuit block 64, and controls the rotation of the motorassembly 136. The detector circuit block 150 further communicates withthe CPU of a personal computer 260, which CPU performs the dataprocessing of the data generated by the spectrophotometric section ofthe whole blood analyzing apparatus and performs the overall control ofthe operation of the apparatus.

The light beam 109 transmitted to the optical fibre fitting 221 andfurther through the optical fibre 220 is emitted from an optical fibrefitting 224 and transmitted through the cuvette 24 and the blood presentwithin the cuvette 24. The light transmitted through the blood withinthe cuvette 24 is received by means of an optical fibre fitting 226 andin further transmitted through an optical fibre 228 to thespectrophotometric section shown in the central part of FIG. 1 below theabove-described dual beam chopper section 100.

The light beam 113 transmitted to the optical fibre fitting 223 andfurther through the optical fibre 222 is also transmitted to thespectrophotometric section. The optical fibre 222 constitutes areference light-transmitting optical fibre. The optical fibre 222 is ofthe same length as the optical fibres 220 and 228 in order to eliminateany influence from differences in optical fibres giving origin tooptical fibre length-dependent attenuation. The optical fibres 228 and222 have their output ends received within an optical fibre connector229, which is shown in FIG. 3, which directs the light received fromeither of the two optical fibres 228 and 222 to a concave holographicgrating 230 of the spectrophotometric section. The spectrophotometricsection is preferably constituted by a spectrophotometer as described inU.S. Pat. No. 4,997,281, to which reference made, and which is herewithincorporated in the present specification by reference.

The light beam emitted from the optical fibre connector 229 andoriginating from one of the fibres 228 and 222 is reflected from themirror 230 and transmitted through a beam-splitting mirror 232 andfocussed by means of lenses 234 and 240 on first and second opticaldetectors 236 and 242, respectively. The first and second opticaldetectors 236 and 242, respectively, are sensitive and responsive toelectromagnetic radiation within the wavelength interval 520-1100 nm and1030-1800 nm, respectively, and are constituted by an array of siliconphotodiodes and array germanium photodiodes, respectively. Each of thearrays contains 76 diodes together providing a 152 incrementalrepresentation of the wavelength interval 520-1800 nm.

The first optical detector 236 is connected to a optical detectorcircuit block 238, including a multiplexing circuit serving the purposeof sequentially presenting the output signals generated by thephotodiodes of the array of photodiodes of the optical detector 236 toan input of an A/D converter 246. Similarly, the second optical detector242 is connected to an optical detector circuit block 244, including amultiplexing circuit, also serving the purpose of sequentiallypresenting the output signals generated by the photodiodes of the arrayof photodiodes of the optical detector 242 to an input of the A/Dconverter 246.

The A/D converter 246 is through its output connected to an input of theCPU of the personal computer 260. The A/D converter 246 is also suppliedwith measuring signals supplied through multiplexing input circuits andrepresenting additional measuring parameters, such as the temperature ofthe spectrophotometric section block and generated by means of atemperature detector.

The components of the spectrophotometric section block are supported ona support block 250, which constitutes a base plate of a thermallyinsulating encasing or housing, not shown in FIG. 1, which isthermostatically controlled by means of a thermostatic controller 252 toa temperature of 16° C. The electronic circuitry of thespectrophotometric section block is powered from a power supply 254.

In FIG. 4, the hose pump 52 and the pivot 24 together with the opticalfibres 220 and 228 connected to the cuvette 24 through the optical fibrefittings 224 and 226, respectively, are shown together with a pulsedetector 86, which is mounted on the hose 26 or alternatively mounted onthe hose 22 adjacent the cuvette 24. The pulse detector 86 is providedwith electrical wires 82 and 84 for establishing electrically conductiveconnection to the PLL synchronizing circuit block 64, shown in FIG. 1,end for supplying electrical signals thereto, representing the bloodflow through the detector and further the variation of the blood flowthrough the hose 26, on which the pulse detector 86 is mounted, andconsequently through the cuvette 24, caused by the pressure fluctuationsgenerated by the hose pump 52, an discussed above. The pulse detector 86may be based on inductive or capacitive detector principles oralternatively based on optical detection technique, as the pulsedetector 86 may comprise light-generating means and light-detectingmeans monitoring the blood flow through the pulse detector based onoptical transmission principles or optical reflection principles or mayfurther alternatively constitute a fibre optic connector, to which twooptical fibres are connected, said optical fibres substituting theelectrical wires 82 and 84.

In FIG. 5 an alternative light transmission technique is shown, as thecuvette 24 is omitted. The hoses 22 and 26 constitute an integral homewhich is clamped between the optical fibre connectors 224 and 226,defining a shallow hose segment 90 of a configuration similar to that ofthe cuvette 24, as the optical fibre connectors 224 and 226 are fixatedby means of a clamping device 225 so an to define a specific spacingbetween the output end of the optical fibre fitting 224 and the inputand of the optical fibre fitting 226.

FIG. 6 illustrates a further, alternative, optical detector technique,according to which the light transmission technique implemented by meansof the optical fibres 222 and 228 is substituted by an optical detectorimplemented in accordance with the optical reflection technique. In FIG.6, an optical detector 92 is shown, which is mounted an the hose 26 andcomprises an input optical fibre 94 and an output optical fibre 96,which optical fibres detect electromagnetic radiation radiated from theoutput and of the optical fibre 94 and reflected from the blood flownthrough the optical detector 92. The optical detector 92 may constitutea component substituting the pulse detector 86, shown in FIG. 4, oralternatively constitute a component replacing the optical transmissiondetector comprising the optical fibres 222 and 228, the optical fibreconnectors 224 and 226, respectively, and further the cuvette 24.

In an alternative embodiment of the optical detector 92, the opticaldetector communicates with a cuvette, such as the cuvette 24, shown inFIGS. 1 and 4 and further in FIG. 14, or an alternative cuvettestructure adapted to allow the blood to flow through the cuvette withoutany substantial pressure or volumetric variations.

In FIG. 2, the dual beam chopper section 100 is shown in greater detailsfurther illustrating a supporting plate 101, on which an optical housing103 is mounted. The optical housing 103 includes the lamp 102, themirrors 104 and 106 and the lenses 108 and 110. FIG. 2 furtherillustrates two filter supports 115 and 117, which support the filters114 and 116, described above FIG. 2 further illustrates the journallingof the chop-per disc 122, which is sandwiched between two brackets 121and 123, which also serve the purpose of supporting the optical fibrefittings 221 and 223 and suer the gear assembly 137, the output shaft138 of which is connected to the chopper disc 122, as the chopper disc122 is mounted on the output shaft 138. In FIG. 2, a printed circuitboard 151 is shown, which constitutes the printed circuit board of thedetector circuit block 150, shown in FIG. 1 and shown in greater detailsin FIG. 8.

In FIG. 3, the spectrophotometric section block is shown. Apart from theoptical fibres 222 and 228 and the optical fibre connector 229, theconcave holographic grating 230 and the beam-splitting mirror 232 areshown. The reference numeral 251 designates a bracket which is rigidlyconnected to the support plate 250 of the spectrophotometer, and thereference numerals 239 and 245 designate printed circuit boardscontaining the electronic circuitry of the first and second opticaldetector circuit blocks 238 and 244, respectively, shown in FIG. 1. Thereference numeral 247 designates a multicore cable which interconnectsthe printed circuit boards 239 and 245 and is further connected to amultipin socket 248 for receiving a mating multipin plug forestablishing electrically conductive connection with the CPU of thepersonal computer 260.

FIG. 7 in a block diagram of the electronic circuitry of thespectrophotometric section shown in the central part of FIG. 1, andfurther shown in FIG. 3. In FIG. 7, the first optical detector 236 isconnected to the first optical detector circuit block 238, which isshown in dotted line in the uppermost part of FIG. 2 and which comprisestwo multichannel preamplifier blocks 268 and 270, the inputs of whichare connected to respective diodes of the diode array of the firstoptical detector 236. The outputs of the multichannel preamplifierblocks 268 and 270 are connected to respective inputs of a muliplexerblock 272, the outputs of which are connected via an optionalprogrammable gain and offset block 274 to the A/D converter block 246,shown in FIG. 1. The control input of block 274 is connected to acontrol output of a digital control block 276. A control input of thedigital control block 276 is connected to the CPU 260 of the personalcomputer controlling the overall operation of the whole blood analyzingapparatus. The A/D converter 246 is also controlled by the digitalcontrol block 276 through a separate control input, which is connectedto a control output of the digital control block 276.

In the lowermost part of FIG. 7, the second optical detector 242 isshown, which is connected to the second optical detector block 244. Thesecond optical detector block 244 is of a topographical configurationsimilar to that of the first optical detector block 238 and comprisestwo multichannel preamplifier blocks 278 and 280 corresponding to themultichannel preamplifier blocks 268 and 270 described above, which arefurther connected to a multiplexer block 282 similar to the multiplexerblock 272 of the first optical detector circuit block 238. Themultiplexer block 282 in via an optional programmable gain and offsetblock 284 similar to the block 274 connected to the A/D converter block246, shown in FIG. 1. The optional programmable gain and offset block284 of the second optical detector circuit block 244 is controlled bythe digital control block 276, which is shared by the two opticaldetector circuit blacks 238 and 244. The multiplexer block 282 is likethe Multiplexer block 272 controlled by the digital control block 276.

The electronic circuitry shown in FIG. 7 is further described in U.S.Pat. No. 4,997,281, to which reference is made, and which is herebyincorporated in the present specification by reference.

FIG. 8 is a block diagram of the detector circuit block 150, the PLLsynchronizing circuit block 64 and further the detectors 140, 143 and146. In the upper left-hand part of FIG. 8, the detectors 140 and 143are shown, each comprising a light-emitting diode 141 and 144,respectively, and a phototransistor 142, 145, respectively. The emitterof the phototransistors 142 and 145 are connected through seriesconfigurations of a light-emitting diode 152 and 154, respectively, anda resistor 156 and 158, respectively, to a positive supply rail of thedetector circuit block 150, and the emitters of the phototransistorswhich constitute NPN transistors are grounded. The light-emitting diodes141 and 144 have their anodes connected through a common series resistor160 to the positive supply rail and have their cathodes grounded.

As one of the phototransistors 142 and 145 receives light emitted fromthe light-emitting diode 141 and 144, respectively, the phototransistorin question starts conducting and causes the potential of the collectorof the phototransistor in question to be lowered from the voltage of thepositive supply rail, causing a shift of a respective detector input pinof a integrated circuit control block 168. The resistors 156 and 158constitute pull-up resistors, which cause the inputs of the integratedcircuit control block 158 connected to the collectors of thephototransistors 162 and 164 to be pulled up to the voltage of thepositive supply rail, to which the resistors 156 and 158 are connectedthrough the LEDs 152 and 154, respectively, provided thephototransistors 142 and 145 are not in their conductive states. Theintegrated circuit control block 168 is provided with addition controlinputs, which are connected through pull-down resistors 182, 184, 186and 188 to ground and further through switches 181, 183, 185 and 187,respectively, to the positive supply rail of the detector circuit block150. The switches 181 and 183 are provided for inverting the signalsoutput from the integrated circuit block 168 to the PLL synchronizingcircuit block 64 to be described in greater details below. The switches185 and 187 are provided for debugging purposes.

The detector 146 is, like the detectors 140 and 143, provided with alight-emitting diode 147 and a phototransistor 148. The anode of thelight-emitting diode 147 is connected to the positive supply rail of thedetector circuit block 150 through a resistor 162, and the junction ofthe cathode of the light-emitting diode 147 and the emitter of thephototransistor 148, which of an NPN configuration, are connected to theground.

The collector of the phototransistor 148 is connected through a pull-upresistor 164 to the positive supply rail and further connected to thenon-inverting input of an operational amplifier 170. The inverting inputof the operational amplifier 170 is connected to an offset compensationpotentiometer 166, which is interconnected between the positive supplyrail of the detector circuit block 150 and the ground. The output of theoperational amplifier 170 is connected through a potentiometer 172 tothe ground, and the wiper of the potentiometer 172 is connected to thebass of an NPN transistor 180, the emitter of which is grounded, and thecollector of which is connected to the positive supply rail through theseries configuration of a light-emitting diode 174 and a resistor 176.The wiper of the potentiometer 172 is also connected to a control inputpin of the integrated circuit control block 168.

In the lower part of FIG. 8, the PLL synchronizing circuit block 64 isshown, which is connected to the switches 60 and 62, mounted an the stembody 54 of the hose pump 50, serving the purpose of detecting therotational operation of the roller support body 54 of the hose pump 50,as described above. The switches 60 and 62 are switchable betweeninoperative states, in which the switches connect the positive supplyrail of the overall eletronic circuitry of the whole blood analyzingapparatus to control inputs of an integrated circuit 66, constituting aflip-flop circuit, and operative states, in which the switches connectthe control inputs of the integrated circuit 66 to the ground. Theoutput of the integrated circuit 66 is connected to a signal input of aPLL synchronizing chip 68, which further has its compensation inputconnected to a control output of the integrated circuit control block168 of the detector circuit block 150. A SNP output terminal of theintegrated circuit 68 is connected through a series configuration of aresistor 70 and a diode 22 to the ground. An output terminal of theintegrated circuit 68 is connected to an VCO input of the integratedcircuit 68 through a resistor 74 and further grounded through acapacitor 76. The VCO input of the integrated circuit 68 is furtherconnected to a non-inverting input of an operational amplifier 78, whichis operated in a unity-gain non-inverting mode, as the output of theoperational amplifier 78 is short-circuited to the inverting input ofthe operational amplifier 78. The output of the operational amplifier 78is connected through a variable resistor 80 to junction at thenon-inverting input of an operational amplifier 196 of the detectorcircuit block 150, the non-inverting input of which is further connectedthrough variable resistors 190, 191 and 192 to output control terminalsof the integrated circuit control block 168 and grounded through aresistor 193.

The output of the operational amplifier 196 is connected through aresistor 198 to the bass of an NPN Darlington power transistor 208, thecollector of which is connected to the positive supply rail of thedetector circuit block 150, and the emitter of which is connectedthrough a series resistor 206 to a pin of a relay contact 215, which inits operative state supplies current through the NPN Darlington powertransistor 208 and the resistor 206 to the motor 136. The collector andthe emitter of the NPN Darlington power transistor 208 areshort-circuited through a capacitor 210 constituting a noise-suppressioncapacitor. The emitter of the NPN Darlington power transistor 208 isfurther connected through a resistor 204 to the base of a NPN transistor200, the collector of which is connected to the base of the NPNDarlington power transistor 208, and the emitter of which is connectedto the relay contact of the relay 215. The transistor 200 constitutes afeedback current-limiting transistor, the emitter of which is connectedthrough a resistor 202 to the inverting input of the operationalamplifier 196, the inverting input of which is further grounded througha resistor 194.

The relay contact 215 is activated by means of a relay coil 214,provided the integrated circuit detector block 168 shifts a separatemotor output low, which output is connected through a resistor 195 tothe base of a NPN relay turn-on resistor 212, the emitter of Which isgrounded, and the collector of which is connected to one terminal of therelay coil 214, the other terminal of which is connected to the positivesupply rail of the detector circuit block 150.

The terminals of the relay coil 214 are further short-circuited througha noise-suppressing capacitor 216. Provided that the relay coil 214 isnot energized, the relay contact 215 short-circuits the motor 136. Asurge-suppression diode 218 is further provided, short-circuiting theterminals of the motor 136.

FIGS. 9, 10, 11, 12 and 13 are diagrams illustrating print-outs producedfrom the measurement of sample fluids which are analyzed by means of thewhole blood analyzing apparatus according to the present invention.

In FIGS. 9, 10, 11, 12 and 13 the abscissa axis represents the pixelnumber 0-151 corresponding to the near infrared wavelength interval520-1800 nm represented by a total of 152 pixels i.e. providing a 152incremental wavelength interval representation of the above 520-1800 nmwavelength interval.

In FIG. 9, the number of counts generated by a specific light detectingelement of a specific pixel corresponding to a specific wavelengthinterval are represented along the ordinate axis. In FIG. 9, threecurves A, B and C are shown representing a sample signal, a referencesignal and a dark signal, respectively.

In FIG. 10, three curves D, E and F are shown representing theabsorbance of glucose, lactate, and urea, respectively, indicated alongthe ordinate axis. For clarity curve D and E are shown offset from curveF. From FIG. 10, it in evident that the peak of pixel no. 120corresponding to the wavelength of 1490 nm of urea is distinguishablefrom the spectra of e.g. glucose and lactate. For illustrating thepossibility of determining urea from e.g. lactate and glucose, thespectra D, E and F are represented in one and the same diagram shown inFIG. 11.

In FIG. 12, two curves G and H are shown representing the absorbance ofoxyhemoglobin and deoxyhemoglobin, respectively. In FIG. 12, fourreferences I, J, K, and L are further shown. The references I and Jrepresent peaks characteristics of deoxyhemoglobin and the reference Krepresents a peak characteristic of oxyhemoglobin. Oxyhemoglobin anddeoxyhemoglobin represent 100 and 0 percentage saturated blood,respectively. The reference L indicates a peak characteristic of water.It is to be realized that the peak L in partly overlapping the peaks ofthe curves D, E, and F shown in FIGS. 10 and 11.

In FIG. 13, a curve M is shown representing the absorbance of a bloodsample. The curve M exhibits the characteristic peak K and L ofoxyhemoglobin also shown in FIG. 12.

In FIG. 14, the cuvette 24 is shown in greater details. The cuvette 24in of a symmetrical structure and comprises a central section 286defining opposite optically transparent plane surfaces together defininga constant flow-through area and an optical transmission path throughthe blood flowing through the cuvette of the order of 0.5-2.0 mm,preferably 1.0 mm. The cuvette 24 is at opposite ends provided withtubular sections 288 and 290 for establishing connection to externalhoses supplying blood to and from the cuvette. Between the tubularsections 288 and 290 and the central section 286 of the cuvette 24,transition sections 289 and 291, respectively, are provided forpreventing that the blood flowing from one of the tubular sections 288and 290 to the central section 286 and vice versa is exposed toexcessive pressure or velocity gradients which might deteriorate theblood.

In FIG. 15, a flow chart of the software of the personal computer isshown, designated the reference numeral 300 in its entirety. Thesoftware centrally comprises a "Main menu block" 302 connected to a"Start block" 304, a "View data block" 312 and an "Exit data block" 316.The "Main menu block" 302 is further connected to an "Acquisition menublock" 314 which is further connected to three blocks, a "Set upparameter block" 306, a "Save data block" 310 and a "Measure data block"308. The "Measure data block" 308 internally comprises a plurality ofprogram steps designated the reference numerals 320-331. The first stepis constituted by a "Measure data block" 320, a second step isconstituted by a "Wait for dark chopper position block" 321 and a thirdstep is constituted by a "Collect dark scan block" 322. A fifth step isconstituted by a "Wait for reference chopper position block" 323, afourth step is constituted by a "Collect reference scan block" 324, asixth step is constituted by a "Wait for dark chopper position block"325, a seventh step is constituted by a "Collect dark scan block" 325,an eigth step is constituted by a "Wait for sample chopper positionblock" 327, a nineth step in constituted by a "Collect sample scanblock" 328, a tenth step is constituted by a "Wait for dark chopperposition block" 329, an eleventh step is constituted by a "Collect darkscan block" 331, and a twelfth step is constituted by a "Decision blockdone? block" 330. Provided the preset number of scans has not beenreached, the program reverts to the fourth measuring step of the "Waitfor reference chopper position block" 323. Provided the preset number ofscans has been reached, the program proceeds to the data "Aquisitionmenu block" 314.

The data aquisition takes place as follows:

The apparatus provides two channels, each supporting a photodiodedetector array constututed by the first and second optical detectors 236and 242, respectively, of 76 pixels and 4 additional auxiliary inputs.The silicon and germanium diode arrays cover the visible and nearinfrared regions of the spectrum from 520 to 1800 nanometers.

For maximum noise suppression, data is collected in time intervals basedon multiples of power line cycles. Pixels are scanned as to permit thesumming of up to eight values of each pixel evenly spaced over the linecycle to enable the contributions of the line frequency to cancel. Theuser is given complete control over the scan sequence via the Scan-Ordertable editor.

Acquired data is currently displayed from memory as tables of numericalvalues. This information may be written to disk for example in the formof ASCII files which may be read into various spread-sheet or spectralinterpretation software packages.

REFERENCES

Ref. 1: Haaland, D. M.; Thomas, E. V. Partial least-square methods forspectral analyses. 1. relation to other quantitative calibration methodsand the extraction of quantitative information Anal Chem 60:1193-1202(1988)

Ref. 2: Haaland, D. M.; Thomas, E. V. Partial least-square methods forspectral analyses. 2. Application to simulated and glass spectral dataAnal Chem 60:1202-1208 (1988)

Ref. 3: Geladi, P.; Kowalski, B. R. Parial least-square: a tutorialAnalytical Chimica Acta 185:1-17 (1986)

Ref. 4: Webster, John G. Encyclopedia of Medical Devices andInstrumentation, Vol. 3: 1695-1711 (1988)

LIST OF REFERENCE NUMERALS

10 Dialysis apparatus

12 Forearm of patient

14 Cannula

16 Hose

18 Arterial pressure monitor

20 Hose

21 Hose loop

22 Hose

24 Cuvette

26 Hose

28 Dialysis fluid inlet hose

30 Dialysis fluid outlet hose

32 Hose

34 Air and foam detector

36 Hose

38 Cannula

40 Dialysis machine

41 Dialysis fluid compartment

42 Blood through-flow compartment

43 Dialysis fluid compartment

44 Blood through-flow compartment

45 Dialysis fluid compartment

50 Hose pump

51 Motor

52 Housing

53 Shaft

54 Roller support body

56 Roller

58 Roller

59 Stem body

60 Switch

61 Electrical signal line

62 Switch

63 Electrical signal line

64 PLL synchronizing circuit block

66 Integrated circuit

68 Integrated circuit

70 Resistor

72 Diode

74 Resistor

76 Diode

78 Operational amplifier

80 Variable resistor

82 Optical fibre or wire

84 Optical fibre or wire

86 Pulse detector

88 Clamping device

90 Hose section

92 Optical detector

94 Optical fibre

96 Optical fibre

98 Power supply

100 Beam-splitting chopper section

101 Supporting plate of beam-splitting chopper section

102 Lamp

103 Optical housing

104 Mirror

106 Mirror

108 Lens

109 First light beam

110 Lens

112 Mirror

113 Second light beam

114 Filter

115 Filter support

116 Filter

117 Filter support

118 Lens

120 Lens

121 Bracket

122 Chopper disc

123 Bracket

124 Protruding rim part

126 Protruding rim part

128 Circumferential recess

130 Circumferential recess

132 Slit

134 Reflecting surface area

136 Motor assembly

137 Gear assembly

138 Output shaft

140 Detector

141 LED

142 Photo-transistor

143 Detector

144 LED

145 Photo-transistor

146 Detector

147 LED

148 Photo-transistor

150 Detector circuit block

151 PCB of detector circuit block

152 LED

154 LED

156 Resistor

158 Resistor

160 Resistor

162 Resistor

164 Resistor

166 Variable resistor

168 Integrated circuit

170 Operational amplifier

172 Variable resistor

174 LED

176 Resistor

180 NPN transistor

181 Switch

182 Resistor

183 Switch

184 Resistor

185 Switch

186 Resistor

187 Switch

188 Resistor

190 Variable resistor

191 Variable resistor

192 Variable resistor

193 Resistor

194 Resistor

195 Resistor

196 Operational amplifier

198 Resistor

200 NPN transistor

202 Resistor

204 Resistor

206 Resistor

208 NPN transistor

210 Capacitor

212 NPN transistor

214 Coil

215 Switch

216 Capacitor

218 Diode

220 Optical fibre

221 Optical fibre fitting

222 Optical fibre

223 Optical fibre fitting

224 Fitting

225 Clamping device

226 Fitting

228 Optical fibre

229 Optical fibre connector

230 Convace holographic grating

232 Beam-splitting mirror

234 Lens

236 First optical detector

238 First optical detector circuit block

239 PCB of first optical detector circuit block

240 Lens

242 Second optical detector

244 Second optical detector circuit block

245 PCB of second optical detector circuit block

246 A/D converter

247 Multicore cable

248 Multipin socket

250 Thermostatically controlled support block

251 Bracket

252 Thermostatical controller

254 Power supply

260 CPU of PC

262 Display of CRT monitor

264 Keyboard

266 Printer

268 Pre-amp

270 Pre-amp

272 Multiplexer

274 Programmable gain and offset block

276 Digital control block

278 Pre-amp

280 Pre-amp

282 Multiplexer

284 Programmable gain and offset block

286 Central section of cuvette 24

288 Tubular section

290 Tubular section

289 Transition section

291 Transition section

300 Software flow chart

302 Main menu block

304 Start block

306 Set up parameter block

308 Measure data block

310 Safe data block

312 View data block

314 Acquisition menu block

316 Exit block

320 Measure data block

321 Wait for dark chopper position block

322 Collect dark scan block

323 Wait for reference chopper position block

324 Collect reference scan block

325 Wait for dark chopper position block

326 Collect dark scan block

327 Wait for sample chopper position block

328 Collect sample scan block

329 Wait for dark chopper position block

330 Decision or done? block

331 Collect dark scan block

We claim:
 1. A method of determining the content of a constituent ofblood of an individual, comprising:extracting a whole blood stream ofthe order of 50-1,000 ml/min from a blood vessel of said individual,directing said whole blood stream through a flow path defining asubstantially non-varying flow-through area and comprising aflow-through measuring cuvette constituting part of said flow path, saidflow-through measuring cuvette including opposite first and secondoptically transparent surface parts defining an optical transmissionpath of the order of 0.5-2.0 mm, propelling said whole blood streamthrough said flow path by means of a pump causing said whole bloodstream to flow through said flow path in a pulsed mode, monitoring saidflow of said whole blood stream through said flow-through measuringcuvette of said flow path, so as to determine periods of substantiallyconstant flow of said whole blood stream through said flow-throughmeasuring cuvette, irradiating said first optically transparent surfacepart of said flow-through measuring cuvette with multi-wavelength nearinfrared light so as to expose said whole blood stream flowing throughsaid flow-through measuring cuvette to said multi-wavelength nearinfrared light, detecting the near infrared absorption spectrumrepresented by near infrared absorption data of said whole blood streamflowing through said flow-through measuring cuvette, and quantifyingsaid content of said constituent by inputting said near infraredabsorption data into a mathematical model representing the relationbetween the near infrared absorption data and the content of saidconstituent.
 2. The method according to claim 1, said non-varyingflow-through area being of the order of 5-20 mm².
 3. The methodaccording to claim 1, said flow-through measuring cuvette comprising acentral section including said opposite first and second opticallytransparent surface parts, tubular inlet and outlet sections and firstand second transition sections, said first and second transitionsections constituting sections connecting said inlet and outletsections, respectively, to said central section and presenting graduallychanging sectional shapes generating to no substantial extent pressureor velocity gradients to said whole blood stream flowing through saidflow-through cuvette so as to eliminate to any substantial extent anyblood degradating pressure or velocity impact to said blood flow.
 4. Themethod according to claim 1, said mathematical model being establishedon the basis of a training set of samples-having relevant knownvariations in composition and thus producing relevant absorptionspectra.
 5. The method according to claim 4, said quantifying of saidcontent of said constituent further comprising any of the followingmathematical analysis techniques: multivariate data analysis technique,e.g. PLS analysis technique (Partial Least Square), PCR analysistechnique (Principal Components Regression), MLR analysis technique(Multiple Linear Regression) or artificial neural network analysistechnique.
 6. A method of determining the content of a constituent ofblood of an individual, comprising:extracting a whole blood stream ofsaid individual from a blood vessel of said individual, directing saidwhole blood stream through a flow path comprising a flow-throughmeasuring cuvette constituting part of said flow path, said flow-throughmeasuring cuvette including at least one, optically transparent surfacepart, propelling said whole blood stream through said flow path by meansof a pump causing said whole blood stream to flow through said flow pathin a pulsed mode, monitoring said flow of said whole blood streamthrough said flow-through measuring cuvette of said flow path, so as todetermine periods of substantially constant flow of said whole bloodstream through said flow-through measuring cuvette, irradiating said atleast one optically transparent surface part of said flow-throughmeasuring cuvette with electromagnetic radiation of a specific spectralcomposition, so as to expose said whole blood stream flowing throughsaid flow-through measuring cuvette to said electromagnetic radiation,detecting the electromagnetic radiation absorption spectrum, representedby electromagnetic radiation absorption data, of said whole blood streamflowing through said flow-through measuring cuvette at said periods ofsubstantially constant flow of said whole blood stream flowing throughsaid flow-through measuring cuvette, and quantifying said content ofsaid constituent by inputting said electromagnetic radiation absorptiondata into a mathematical model representing the relation betweenelectromagnetic radiation absorption data and the content of saidconstituent.
 7. The method according to claim 6, said flow-throughmeasuring cuvette comprising opposite first and second opticallytransparent surface parts and defining a substantially non-varyingoptical transmission path, and said detection of said electromagneticradiation absorption spectrum being determined by detecting thetransmission of said electromagnetic radiation through said whole bloodstream flowing through said flow-through measuring cuvette through saidoptical transmission path thereof.
 8. An apparatus for determining thecontent of a constituent of blood of an individual, comprising:means forextracting a whole blood stream from a blood vessel of said individual,a flow path defining a substantially non-varying flow-through area,means for directing said whole blood stream through said flow path, aflow-through measuring cuvette constituting a part of said flow path,said flow-through measuring cuvette including opposite first and secondoptically transparent surface parts defining an optical transmissionpath of the order of 0.5-2.0 mm, pump means for propelling said wholeblood stream through said flow path causing said whole blood stream toflow through said flow path in a pulsed mode, means for monitoring saidflow of said whole blood stream through said flow-through measuringcuvette of said flow path, so as to determine periods of substantiallyconstant flow of said whole blood stream flowing through saidflow-through measuring cuvette, means for generating and irradiatingsaid first optically transparent surface part of said flow-throughmeasuring cuvette with multi-wavelength near infrared light so as toexpose said whole blood stream flowing through said flow-throughmeasuring cuvette to said multi-wavelength near infrared light, detectormeans for detecting the near infrared absorption spectrum of said wholeblood stream flowing through said flow-through measuring cuvetterepresented by near infrared absorption data, and quantifying means forquantifying said content of said constituent by inputting said nearinfrared absorption data into a mathematical model representing therelation between near infrared absorption data and the content of saidconstituent.
 9. The apparatus according to claim 8, said non-varyingflow-through area being of the order of 5-20 mm².
 10. The apparatusaccording to claim 8, said flow-through measuring cuvette comprising acentral section including said opposite first and second opticallytransparent surface parts, tubular inlet and outlet sections and firstand second transition sections, said first and second transitionsections constituting sections connecting said inlet and outletsections, respectively, to said central section and presenting graduallychanging sectional shapes generating to no substantial extent pressureor velocity gradients to said whole blood stream flowing through saidflow-through cuvette so as to eliminate to any substantial extent anyblood degradating pressure or velocity impact to said blood flow. 11.The apparatus according to claim 8, said mathematical model beingestablished on the basis of a training set of samples having relevantknown variations in composition and thus producing relevant absorptionspectra.
 12. The apparatus according to claim 11, said quantifying ofsaid content of said constituent further comprising any of the followingmathematical analysis techniques: multivariate data analysis technique,e.g. PLS analysis technique (Partial Least Square), PCR analysistechnique (Principal Components Regression), MLR analysis technique(Multiple Linear Regression) or artificial neural network analysistechnique.
 13. An apparatus for determining the content of a constituentof blood of an individual, comprising:means for extracting a whole bloodstream of said individual from a blood vessel of said individual, a flowpath, means for directing said whole blood stream through said flowpath, a flow-through measuring cuvette constituting part of said flowpath, said flow-through measuring cuvette including at least oneoptically transparent surface part, means for propelling said wholeblood stream through said flow path, causing said flow-path to flowthrough said flow path in a pulsed mode, monitor means for monitoringsaid flow of said whole blood stream through said flow-through measuringcuvette of said flow path, so as to determine periods of substantiallyconstant flow of said whole blood stream flowing through saidflow-through measuring cuvette, means for generating and irradiatingsaid at least one optically transparent surface part of saidflow-through measuring cuvette with electromagnetic radiation of aspecific spectral composition, so as to expose said whole blood streamflowing through said flow-through measuring cuvette to saidelectromagnetic radiation of said specific spectral composition,detector means for detecting the electromagnetic radiation absorptionspectrum, represented by electromagnetic radiation absorption data, ofsaid whole blood stream flowing through said flow-through measuringcuvette at said periods of substantially constant flow of said wholeblood stream flowing through said flow-through measuring cuvette, andquantifying means for quantifying said content of said constituent byinputting said electromagnetic radiation absorption data into amathematical model representing the relation between electromagneticradiation absorption data and the content of said constituent.
 14. Theapparatus according to claim 13, said mathematical model beingestablished on the basis of a training set of samples having relevantknown variations in composition and thus producing relevant absorptionspectra.
 15. The apparatus according to claim 14, said quantifying ofsaid content of said constituent further comprising any of the followingmathematical analysis techniques: multivariate data analysis technique,e.g. PLS analysis technique (Partial Least Square), PCR analysistechnique (Principal Components Regression), MLR analysis technique(Multiple Linear Regression) or artificial neural network analysistechnique.
 16. A method of hemodialysis treatment, comprising:extractinga whole blood stream of the order of 50-1,000 ml/min from a blood vesselof an individual, directing said whole blood stream through anextracorporeal flow path to a hemodialyser through a flow pathcomprising a flow-through measuring cuvette constituting part of saidflow path, said flow-through measuring cuvette including opposite firstand second optically transparent surface parts defining an opticaltransmission path of the order of 0.5-2.0 mm, propelling said wholeblood stream through said flow path by means of a pump causing saidwhole blood stream to flow through said flow path in a pulsed mode,monitoring said flow of said whole blood stream through saidflow-through measuring cuvette of said flow path, so as to determineperiods of substantially constant flow of said whole blood streamthrough said flow-through measuring cuvette, irradiating said firstoptically transparent surface part of said flow-through measuringcuvette with multi-wavelength near infrared light comprising light ofthe wavelength range 700-1,800 nm so as to expose said whole bloodstream flowing through said flow-through measuring cuvette to saidmulti-wavelength near infrared light, detecting the near infraredabsorption spectrum of said whole blood stream flowing through saidflow-through measuring cuvette represented by near infrared absorptiondata, quantifying the content of urea of said whole blood stream byinputting said near infrared absorption data into a mathematical modelrepresenting the relation between near infrared absorption data and thecontent of urea.
 17. The method according to claim 16, said flow pathdefining a substantially non-varying flow-through area.
 18. The methodaccording to claim 17, said non-varying flow-through area being of theorder of 5-20 mm².
 19. The method according to claim 16, furthercomprising continuing said hemodialysis treatment until the content ofurea of said whole blood stream has decreased below a specificthreshold.
 20. The method according to claim 19, said flow-throughmeasuring cuvette comprising a central section including said oppositefirst and second optically transparent surface parts, tubular inlet andoutlet sections and first and second transition sections, said first andsecond transition sections constituting sections connecting said inletand outlet sections, respectively, to said central section andpresenting gradually changing sectional shapes generating to nosubstantial extent pressure or velocity gradients to said whole bloodstream flowing through said flow-through cuvette so as to eliminate toany substantial extent any blood degradating pressure or velocity impactto said blood flow.
 21. The method according to claim 19, saidmathematical model being established on the basis of a training set ofsamples having relevant known variations in composition and thusproducing relevant absorption spectra.
 22. The method according to claim21, said quantifying of said content of said constituent furthercomprising any of the following mathematical analysis techniques:multivariate data analysis technique, e.g. PLS analysis technique(Partial least Square), PCR analysis technique (Principal ComponentsRegression), MLR analysis technique (Multiple Linear Regression) orartificial neural network analysis technique.